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Saturday, September 5, 2009

By examining blood samples donated by infected people in developing countries, US researchers have found two new powerful antibodies to HIV that open the door to a new and effective AIDS vaccine. The antibodies, called PG9 and PG16, are of a type known as bNAbs (broadly neutralizing antibodies) and exploit an "Achilles heel" or vulnerable spot in the HIV that could be an effective target for a vaccine, said the researchers.

The discovery was made by researchers working at and with the International AIDS Vaccine Initiative (IAVI), at The Scripps Research Institute, and at the biotechnology companies Theraclone Sciences and Monogram Biosciences, and was published on 3 September as an online advanced issue in Science.

Co-principal investigator Wayne Koff, who is senior vice president of research and development at IAVI in New York, told the media:

"The findings themselves are an exciting advance toward the goal of an effective AIDS vaccine because now we've got a new, potentially better target on HIV to focus our efforts for vaccine design."

He said now they've found this target they can look for more, and speed up global efforts to develop an effective AIDS vaccine.

The discovery relied on a global collaboration that developed a new way of looking for bNAbs, and the researchers fully expect more to be found, revealing further vulnerable spots on HIV for vaccines to target.

Only a small proportion of people infected with HIV produce bNAbs, a range of antibodies that are different to other antibodies because they effectively neutralize a high proportion of the HIV types in circulation around the world.

Animal experiments suggest that if the body can "learn" to produce these types of antibody, which is what an effective AIDS vaccine induces, then it is able to protect itself from infection by HIV.

Other bNAbs against HIV have been discovered before, but PG9 and PG16 are the first to be isolated in over 10 years from donors in developing countries, where most new HIV infections occur. Also, the previously identified bNAbs bind to spots on the virus that are hard to target with vaccines.

One of the other co-principal investigators, Dennis Burton, who is professor of immunology and microbial science and scientific director of the IAVI Neutralizing Antibody Center at The Scripps Research Institute in La Jolla, California, said:

"These new antibodies, which are more potent than other antibodies described to date while maintaining great breadth, attach to a novel, and potentially more accessible site on HIV to facilitate vaccine design."

"So now we may have a better chance of designing a vaccine that will elicit such broadly neutralizing antibodies, which we think are key to successful vaccine development," added Burton, who is also a member of the newly established Ragon Institute of MGH, MIT and Harvard.

For a vaccine to be effective it must be able to stimulate the immune system to make broad spectrum antibodies that can effectively neutralize as many forms of the virus as possible. Ability to stimulate high potency antibodies also makes it more likely that the vaccine does not need to stimulate production of too many antibodies to make it effective.

One of the features of HIV that gives it an advantage, is a viral "spike" that it uses to invade cells. The "spike" foils attack by the immune system because it relies on two glycoproteins, gp120 and gp41, which keep changing. This is a successful tactic for HIV because by the time the immune system has noticed the new version of the spike and made new antibodies to attack it, the virus has invaded enough host cells to allow it to replicate in large numbers and overwhelm the immune system.

But PG9 and PG16 attack a part of the "viral spike" of the HIV: specifically they attack regions of gp120 that don't change, and this is probably why they are broad spectrum neutralizers.

There are probably two main reasons why the researchers were able to discover PG9 and PG16: one was the high number of blood samples they were able to access from a range of developing countries, and the other was they used a new way of testing whether bNAbs bind to gp120 and gp41.

The blood samples the researchers used were donated by HIV-infected volunteers from IAVI-supported clinical research centers based in seven sub-Saharan countries as well as in Thailand, Australia, the UK and the US.

The conventional way of testing the ability of bNAbs to bind to gp120 and gp41 uses soluble forms of the proteins, and if Koff, Burton and colleagues had used it they would probably have rejected PG9 and PG16 as candidate bNAbs because they bind weakly to soluble forms of the proteins. But they used a new method that relies on a micro-neutralization assay developed jointly by Monogram Biosciences and IAVI which they ran in parallel with the standard binding assays.

This new method is likely to make a significant difference to the way bNAbs are screened in the future, because it allows researchers to screen bNAbs directly for their ability to block HIV infection.

Another important aspect of the work was the contribution of Theraclone Sciences, a company that was initially working outside of the HIV field, but they had a relevant and unique high throughput process that could be adapted to isolate the effective bNAbs in a much shorter time. Funding from IAVI's Innovation Fund, which is co-funded by the Bill & Melinda Gates Foundation helped to pay for the adaptation.

The process that the Theraclone team used exposes all the antibodies in a blood sample from an HIV infected person, identifies those with broadly neutralizing potential and traces them to their corresponding antibody-forming cells. With recombinant DNA technology, they isolated genes from the candidate bNAbs so they could clone them in large numbers for testing.

Monday, May 25, 2009

The US Centers for Disease Control and Prevention (CDC) said that there is a "global need for more systemic surveillance of influenza viruses in pigs", during a press briefing where they explained the findings of a recent study on the genetic and antigenetic properties of the new 2009 H1N1 swine flu virus.

The CDC led study was published online in the journal Science on 22 May and was the work of human and animal health scientists from the US, Mexico, the UK and the Netherlands.

According to the CDC, the study is the first to explain the history and evolution of the human and swine influenza viruses in North America and other areas of the world, as deduced from the detailed analysis of the antigenic and genetic characteristics of the new H1N1 viruses.

In a press briefing on Friday, senior author Dr. Nancy Cox, who is director of the CDC's influenza division said that the study reinforced the fact that:

"Swine are an important reservoir of influenza viruses with the potential to cause significant respiratory outbreaks or even a possible pandemic in humans."

Cox praised the "excellent collaboration" that went into the study, and stressed the importance of the global co-operation that will be needed to fight the new H1N1 strain, for example by rapidly collecting and sharing specimens, without which it is not possible to understand the origin of the virus and how to stop it spreading and re-emerging.

For the study, the researchers sequenced the genomes of more than 70 samples of the new H1N1 taken from human patients diagnosed with the infection in the recent outbreaks, including 17 viruses isolated in Mexico and 59 viruses from 12 states in the United States.

The analysis showed that the new H1N1 virus likely originated in pigs because each of its genetic components closely corresponds to genes found in swine flu viruses, said Cox, who then highlighted the study's main findings:

The new H1N1 viruses are very alike in the way they react to antibodies, that is their antigenetic properties are similar. However, in this respect they are very different to human H1N1 viruses (like the seasonal flu virus), so this indicates that the seasonal flu vaccine will probably not protect against the new virus, a fact that the CDC announced last week.

The fact the new H1N1 strains are very similar means that it will be much easier to come up with a new candidate virus for vaccine development (there are already reports that a lab has sent a sample candidate virus to the CDC). Cox said as far as they could tell, the new H1N1 swine flu viruses varied much less among themselves than say the typical seasonal flu viruses do.

From their resistance patterns it appears that the new H1N1 viruses are sensitive to the neuraminidase inhibitors, but resistant to the M2 blockers or rimantidine (Flumadine) and amantadine (Symmetrel). This is important information for the development and use of antivirals.

As revealed in previous press briefings, the new virus also contained clusters of gene segments that had not been seen in swine or human flu viruses before. A noticeable new feature was that two gene segments, one from a matrix protein and the other from a nerve gene, seemed to have come from Eurasian swine viruses not seen outside of Eurasia before.

While the analysis shows that all gene segments came from swine flu viruses, it was not possible to say if the virus then went straight into humans or via an intermediate host, and if it did go via a host, then which animal that would be.

Animal scientists all over the world, including colleagues from the US Department of Agriculture (USDA) are testing samples they have kept frozen for years to see if they can provide any missing links to this part of the puzzle. For instance, there might be intermediate versions of the virus that could help narrow down the time and place where the new virus emerged.

When asked if these findings mean that pig surveillance will now be as important as avian surveillance as far as flu virus monitoring was concerned, Dr. Anne Schuchat, director of CDC's national center for immunization and respiratory diseases, said:

"This really hits home how important it is for animal and human health to cooperate and collaborate."

She said she and her colleagues at the CDC were very pleased at how the collaboration between animal and human health has improved, implying it was vital to continue this because as the past few decades have shown, "the animal-human interface is very important".

Wednesday, March 4, 2009

Moves to restrict researchers' access to patient record data will undermine patient care, say top researchers in an article published by the medical journal Pulse. Heads of some of the UK's top research organizations warn that over-protectiveness over the safety of public data will result in UK patients not having access to clinical trials treatments.

The UK government has dropped a key pledge to grant researchers the right in the NHS constitution to access identifiable medical records without needing to get patient consent - this was after an uproar among General Practitioners (GPs).

In order to select clinical trial participants, the researchers say it is essential to be able to access patient data without having to seek consent first. The researchers suggest safe havens be set up so they might access anonymous patient data.

Sir Mark Walport, director of the Wellcome Trust - said the NHS Constitution was "going in the right direction" but Government was dithering over allowing access to anonymous patient data. "It is becoming harder and harder to do research that was previously easy to do. If you actually explain to patients about how their data is going to be used, then they are happy for it to be used."

Sir Mark says the argument is being distorted by concern over high profile data leaks from government agencies "None of these were related to medical research - not one," he said.

Professor Peter Weissberg, Medical Director, British Heart Foundation, said patients could gain access to "gold standard" treatment in clinical trials, but this was being jeopardized by Government moves to curb access to medical records.

Weissberg added "We run the risk of unpicking everything that we have done before, and we may not be able to do landmark studies such as the Heart Protection Study in this country."

Mesothelioma is a form of lung cancer that is almost always caused by asbestos exposure and is most commonly found in the outer lining of the lungs called the mesothelium. A majority of the people who develop mesothelioma contract this cancer through breathing in asbestos fibers or being exposed to asbestos dust while on the job. In cases where mesothelioma is found in a person with no previous occupational exposure, it is summarized that the exposure may have stemmed from asbestos fibers found on the clothes of someone in their home who worked in an area where asbestos dust was found.

There are a number of reasons that make diagnosing mesothelioma in its early stages extremely difficult. The symptoms of mesothelioma can have a latency period of anywhere between 20 to 50 years after the initial asbestos contact, which means by the time the symptoms begin to show, the cancer is already within its advanced stages. Once symptoms are present, diagnosis is still not a speedy process. There are a number of diseases that mirror the symptoms that are found in mesothelioma patients and because of this mesothelioma is often the last stop - usually without prior mention from the patient about the possibility of previous asbestos exposure.

The success of treatment for mesothelioma is dependent on the stage in which the cancer is found. As it is found that most mesothelioma is not discovered until the advanced stages, mesothelioma treatment is often referred to as "unsuccessful." Studies show that when found within either stage I or II, treatment for mesothelioma - usually with a combination of radiation and chemotherapy - is successful in extending the patient's life for five years at a rate of 74.6% (Wikipedia). There are also alternative forms of therapy that can be used in conjunction with conventional treatments, that have been shown on occasion to decrease the size of mesothelioma found in a patient.

Asbestos was used for many years in a wide array of household and industrial products because of its multiple types and uses. It is fireproof, and can also be used as an insulator, thus allowing it to become very popular during the Industrial Revolution. It is unknown whether or not people were aware of the dangers of asbestos fibers at that time, but by the 1900's the risk of asbestos was becoming more obvious. People who lived in mining towns would develop lung problems, and general studies showed that asbestos workers died at a young age. Asbestos, in an undisturbed state, seems to pose no threat. However, as soon as it becomes damaged or friable, the fibers are able to be ingested, thus potentially leading to these or other health problems. Although some companies were aware of this danger, they continued to work with products containing asbestos with no regard to their employees. These blatant injustices are the reason for the popularity of mesothelioma in the field of litigation.

A new study in this week´s PLoS Medicine, reports that the risk of suicide increases two to three time on young men 24 years old or less who leave the UK Armed Forces than those remaining in active service or those in the general population.

In the first two years after discharge, the risk seems to increase in the men with short length of service, and those of inferior rank. Just 14 percent of 20 years old or less and 20 percent of 24 years old or under, had communication with mental health specialists in the year prior to their death, according to the study.

Nav Kapur, Center for Suicide Prevention, University of Manchester, UK, and his team, conducted a cohort study, using data from the National Confidential Inquiry into Suicide and Homicide in connection to all the people who left the UK Armed Forces between 1996 and 2005. The Inquiry, since 1996, has been gathering data on all the suicides in the UK, as well as whether the deceased had contact with mental health services in the year prior to death. Of the 233,803 individuals who left the Armed Forces, 224 committed suicide, during the study period.

The overall suicide rate of the ex-military personnel was comparable to that of the general population, according to the study. Although the absolute risk of suicide is small (in 16 to 19 years old, the rate of suicide was of 29.9 per 100,000 persons and in 20 to 24 years old, 34.0 per 100,000 persons), the rate was higher for younger men.

The cause for the higher risk in young men was not established in the study but researchers point out three key potential elements: -Anxiety due to transition to civilian life -Experience of difficult circumstances while in the military -Vulnerability to suicide prior to enrolling in the military According to the study, there is some proof to confirm the third possibility, since inexpert recruits leaving the military after short lengths of service were at highest risk of suicide. The increased risk may reveal a pre-military weakness.

Kapur and his team suggest suicide prevention strategies should be targeted to young people leaving the military. They say these might incorporate "practical and psychological preparation for discharge and encouraging appropriate help-seeking behavior once individuals have left the services".

Jitender Sareen and Shay-Lee Belik, University of Manitoba, Winipeg Canada, who are both unrelated to the study, underline in an expert commentary, the example of the US Air Force which has a suicide program for the exposed military population. They also reflect on suicide prevention in general public health.